Mechanical cardiopulmonary resuscitation for venoarterial ECMO implantation in pulmonary embolism complicated by type B aortic dissection and retroperitoneal hemorrhage.

A patient with acute pulmonary embolism suffered cardiac arrest, received manual and mechanical cardiopulmonary resuscitation and tissue plasminogen activator before extracorporeal cardiopulmonary resuscitation was initiated. She suffered a type B aortic dissection and retroperitoneal hemorrhage secondary to resuscitation measures. This case report describes high-risk anticoagulation management for contradicting treatment goals in preparation for pulmonary embolectomy on cardiopulmonary bypass.

Is Direct Endovascular Treatment as an Alternative of Bridging Therapy in Acute Stroke Patients with Large Vessel Occlusion?

BACKGROUND: Although endovascular treatment (EVT) is very effective for acute ischemia stroke (AIS) patients with proximal large vessels occlusion (LVO), whether bridging rPA before EVT in stroke patients of LVO is of any benefit and is currently one of the most urgent unanswered questions. We aim to comprehensively determine the efficacy and safety of direct EVT (DEVT) in AIS patients with LVO versus bridging therapy (BT). METHODS: Clinical researches published in the Embase, PubMed, and Cochrane Library electronic databases up to May 2017 were identified for analysis. Two reviewers extracted data and conducted quality assessment independently. Statistical tests were performed to check for heterogeneity and publication bias. Subgroup and sensitivity analysis were also conducted to evaluate the robustness of the conclusions. RESULTS: Overall, 13 studies involving 3302 patients met the inclusion criteria. The AIS patients with DEVT had a similar likelihood to achieve good functional outcome at 3 months (risk ratio [RR] = .93, 95% confidence interval [CI] = .85-1.01, P = .094), mortality at 3 months (RR = 1.10, 95% CI = .91-1.33, P = .33), and symptomatic intracranial hemorrhage (RR = 1.06, 95% CI = .74-1.51, P = .75) versus BT; furthermore, the risk of intracranial hemorrhage was lower in DEVT group (RR = .76, 95% CI = .60-.95, P = .02). No significant difference in recanalization rate existed between the 2 groups (RR = .97, 95% CI = .92-1.02, P = .22); however, in the subgroup analysis, it had a rise trend after DEVT than BT in IVT-eligible group (RR = 1.45, 95% CI = .95-2.22, P = .09). CONCLUSIONS: DEVT appears to have equally effectiveness to BT with a low risk of intracranial hemorrhage in AIS patients with LVO, especially for anterior circulation, which offered a practical information to select appropriate therapeutic strategies for patients with LVO, though the level of evidence seems to be quite shaky.

Desmoteplase 3 to 9 Hours After Major Artery Occlusion Stroke: The DIAS-4 Trial (Efficacy and Safety Study of Desmoteplase to Treat Acute Ischemic Stroke).

BACKGROUND AND PURPOSE: The DIAS-3 trial (Efficacy and Safety Study of Desmoteplase to Treat Acute Ischemic Stroke [phase 3]) did not demonstrate a significant clinical benefit of desmoteplase administered 3 to 9 hours after stroke in patients with major artery occlusion. We present the results of the prematurely terminated DIAS-4 trial together with a post hoc pooled analysis of the concomitant DIAS-3, DIAS-4, and DIAS-J (Japan) trials to better understand the potential risks and benefits of intravenous desmoteplase for the treatment of ischemic stroke in an extended time window. METHODS: Ischemic stroke patients with occlusion/high-grade stenosis in major cerebral arteries were randomly assigned to intravenous treatment with desmoteplase (90 µg/kg) or placebo. The primary outcome was modified Rankin Scale (mRS) score of 0 to 2 at day 90. Safety assessments included mortality, symptomatic intracranial hemorrhage, and other serious adverse events. RESULTS: In DIAS-4, 52 of 124 (41.9%) desmoteplase-treated and 46 of 128 (35.9%) placebo-treated patients achieved an mRS score of 0 to 2 (odds ratio, 1.45; 95% confidence interval, 0.79; 2.64; P=0.23) with equal mortality, frequency of symptomatic intracranial hemorrhage, and other serious adverse events in both the treatment arms. In the pooled analysis, mRS score of 0 to 2 was achieved by 184 of 376 (48.9%) desmoteplase-treated versus 171 of 381 (44.9%) placebo-treated patients (odds ratio, 1.33; 95% confidence interval, 0.95; 1.85; P=0.096). Treatment with desmoteplase was safe and increased the recanalization rate (107/217 [49.3%] versus 85/222 [38.3%]; odds ratio, 1.59; 95% confidence interval, 1.08-2.35; P=0.019). Recanalization was associated with favorable outcomes (mRS 0-2) at day 90 in both the treatment arms. CONCLUSIONS: Late treatment with intravenous 90 µg/kg desmoteplase is safe, increases arterial recanalization, but does not significantly improve functional outcome at 3 months. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00856661.

Safety and Tolerability of Desmoteplase Within 3 to 9 Hours After Symptoms Onset in Japanese Patients With Ischemic Stroke.

BACKGROUND AND PURPOSE: This study investigated the safety and tolerability of desmoteplase administered within 3 to 9 hours after stroke symptoms onset in Japanese patients with acute ischemic stroke. METHODS: Patients were randomized to treatment with either desmoteplase or placebo in a 2:1 ratio in 2 consecutive cohorts (70 µg/kg and then 90 µg/kg). Included patients had a baseline National Institutes of Health Stroke Scale score of 4 to 24 and occlusion or high-grade stenosis in the middle cerebral artery segment M1 or M2 on magnetic resonance angiography. The incidence of symptomatic intracranial hemorrhage (≤72 hours) was defined as the primary end point. The occurrence of asymptomatic ICH, symptomatic cerebral edemas, and adverse events were other safety outcomes of special interest. RESULTS: Symptomatic intracranial hemorrhage was observed within 72 hours in 2 patients treated with placebo and in 1 patient treated with 70 µg/kg desmoteplase. Any ICH (symptomatic or asymptomatic ICH) within 72 hours were observed in 7 (43.8%) patients treated with placebo, in 8 (50%) patients treated with 70 µg/kg desmoteplase, and in 9 (56.3%) patients treated with 90 µg/kg desmoteplase. Desmoteplase treatment with 70 or 90 µg/kg was not associated with an increased risk of symptomatic cerebral edema compared with placebo. There were no other serious safety concerns associated with desmoteplase. CONCLUSIONS: Desmoteplase in both 70 and 90 µg/kg doses had a favorable safety profile and was well tolerated in Japanese patients with acute ischemic stroke when administered 3 to 9 hours after stroke symptoms onset. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01104467.

What causes intracerebral bleeding after thrombolysis for acute ischaemic stroke? Recent insights into mechanisms and potential biomarkers.

The overall population benefit of intravascular recombinant tissue plasminogen activator (rtPA) on functional outcome in ischaemic stroke is clear, but there are some treated patients who are harmed by early symptomatic intracranial haemorrhage (ICH). Although several clinical and radiological factors increase the risk of rtPA-related ICH, none of the currently available risk prediction tools are yet useful for practical clinical decision-making, probably reflecting our limited understanding of the underlying mechanisms. Finding new methods to identify patients at highest risk of rtPA-related ICH, or new measures to limit risk, are urgent challenges in acute stroke therapy research. In this article, we focus on the potential underlying mechanisms of rtPA-related ICH, highlight promising candidate risk biomarkers and suggest future research directions.

Vascular occlusion enables selecting acute ischemic stroke patients for treatment with desmoteplase.

BACKGROUND AND PURPOSE: Desmoteplase is a novel and highly fibrin-specific thrombolytic agent. Evidence of safety and efficacy was obtained in 2 phase II trials (Desmoteplase In Acute Ischemic Stroke [DIAS] and Desmoteplase for Acute Ischemic Stroke [DEDAS]). The DIAS-2 phase III trial did not replicate the positive phase II efficacy findings. Post hoc analyses were performed with the aim of predicting treatment responders based on CTA and MRA. METHODS: Patients were grouped according to vessel status (Thrombolysis In Myocardial Infarction [TIMI] grade) for logistic regression of clinical response, applying the data from DIAS-2 as well as the pooled data from DIAS, DEDAS, and DIAS-2. RESULTS: In DIAS-2, a substantial number of mismatch-selected patients (126/179; 70%) presented with a normal flow/low-grade stenosis (TIMI 2-3) at screening, with the majority having a favorable outcome at day 90. In contrast, favorable outcome rates in patients with vessel occlusion/high-grade stenosis (TIMI 0-1) were 18% with placebo versus 36% and 27% with desmoteplase 90 and 125 µg/kg, respectively. The clinical effect based on the pooled data from DIAS, DEDAS, and DIAS-2 was favorable for desmoteplase-treated patients presenting with TIMI 0 to 1 at baseline (OR, 4.144; 95% CI, 1.40-12.23; P=0.010). There was no desmoteplase treatment benefit in patients presenting with TIMI 2 to 3 (OR, 1.109). CONCLUSIONS: In this sample of patients with a mismatch diagnosed, proximal vessel occlusion or severe stenosis was associated with clinically beneficial treatment effects of desmoteplase. Selecting patients using CTA or MRA in clinical trials of thrombolytic therapy is justifiable.

Observational investigation of thrombolysis with the tissue-type plasminogen activator monteplase for acute pulmonary embolism in Japan.

BACKGROUND: In Japan, the safety and efficacy of thrombolytic therapy using tissue-type plasminogen activator for acute pulmonary embolism (PE) in the real world remain unclear. METHODS AND RESULTS: A total of 1,254 patients with acute PE covered by the post-marketing surveillance of thrombolytic therapy using monteplase were divided into 3 groups: cardiopulmonary arrest (CPA)/collapse group (n=85); massive group, patients with unstable hemodynamics without CPA/collapse (n=217); and submassive group, patients with stable hemodynamics and right ventricular dysfunction (RVD) (n=465). In the efficacy analysis of 767 cases, the response rate to monteplase was 94.6% according to pulmonary circulation assessment and 93.3% according to clinical efficacy judged by symptoms and signs. Overall survival rates at 30 days after monteplase administration were 89.2% overall, 41.2% for the CPA/collapse group, 93.0% for the massive group, and 96.3% for the submassive group. When the safety of monteplase was analyzed in 1,241 cases, severe bleeding complications occurred in 100 patients (8.1%). Intracranial hemorrhage (ICH) occurred in 21 patients (1.7%), but no significant independent predictors were found in multivariate analysis. CONCLUSIONS: Thrombolytic therapy is highly effective in Japanese acute PE patients and offers acceptable safety, but attention is needed regarding severe bleeding complications, including ICH.

Clinical Pharmacokinetics and Pharmacodynamics of Desmoteplase.

Desmoteplase is a bat (Desmodus rotundus) saliva-derived fibrinolytic enzyme resembling a urokinase and tissue plasminogen activator. It is highly dependent on fibrin and has some neuroprotective attributes. Intravenous administration of desmoteplase is safe and well tolerated in healthy subjects. Plasma fibrinolytic activity is linearly related to its blood concentration, its terminal elimination half-life ranges from 3.8 to 4.92 h (50 vs. 90 µg/kg dose). Administration of desmoteplase leads to transitory derangement of fibrinogen, D-dimer, alpha2-antiplasmin, and plasmin and antiplasmin complex which normalize within 4-12 h. It does not alter a prothrombin test, international normalized ratio, activated partial thromboplastin time, and prothrombin fragment 1.2. Desmoteplase was tested in myocardial infarction and pulmonary embolism and showed promising results versus alteplase. In ischemic stroke trials, desmoteplase was linked to increased rates of symptomatic intracranial hemorrhages and case fatality. However, data from "The desmoteplase in Acute Ischemic Stroke" Trials, DIAS-3 and DIAS-J, suggest that the drug is well tolerated and its safety profile is comparable to placebo. Desmoteplase is theoretically a superior thrombolytic because of high fibrin specificity, no activation of beta-amyloid, and lack of neurotoxicity. It was associated with better outcomes in patients with significant stenosis or occlusion of a proximal precerebral vessels. However, DIAS-4 was stopped as it might have not reached its primary endpoint. Due to its promising properties, desmoteplase may be added into treatment of ischemic stroke with extension of the time window and special emphasis on patients presenting outside the 4.5-h thrombolysis window, with wake-up strokes and strokes of unknown onset.

Matrix metalloproteinase-9 as a marker for acute ischemic stroke: a systematic review.

Matrix metalloproteinase-9 (MMP-9) is a possible marker for acute ischemic stroke (AIS). In animal models of cerebral ischemia, MMP expression was significantly increased and was related to blood-brain barrier disruption, vasogenic edema formation, and hemorrhagic transformation. The definition of the exact role of MMPs after ischemic stroke will have important diagnostic implications for stroke and for the development of therapeutic strategies aimed at modulating MMPs. The objectives of the present study were to determine (1) whether MMP-9 is a possible marker for AIS; (2) whether MMP-9 levels correlate with infarct volume, stroke severity, or functional outcome; and (3) whether MMP-9 levels correlate with the development of hemorrhagic transformation after tissue plasminogen activator (t-PA) administration. The literature was searched using MEDLINE and EMBASE with no year restriction. All relevant reports were included. A total of 22 studies (3,289 patients) satisfied the inclusion criteria. Our review revealed that higher MMP-9 values were significantly correlated with larger infarct volume, severity of stroke, and worse functional outcome. There were significant differences in MMP-9 levels between patients with AIS and healthy control subjects. Moreover, MMP-9 was a predictor of the development of intracerebral hemorrhage in patients treated with thrombolytic therapy. MMP-9 level was significantly increased after stroke onset, with the level correlating with infarct volume, stroke severity, and functional outcome. MMP-9 is a possible marker for ongoing brain ischemia, as well as a predictor of hemorrhage in patients treated with t-PA.

Carotid duplex ultrasonography can predict outcome of intravenous alteplase therapy for hyperacute stroke.

We evaluated whether carotid duplex ultrasonography (US) can help predict the safety and efficacy of treating hyperacute stroke with intravenous (IV) tissue plasminogen activator (alteplase) therapy. Consecutive patients with stroke were assigned to the carotid artery occlusion (CO) group or the other (non-CO) group according to US findings before or immediately after receiving IV alteplase. Effectiveness and safety outcomes included early neurologic improvement, defined as a reduction in a National Institutes of Health Stroke Scale (NIHSS) score of ≥4 points within the initial 24 hours after stroke onset; completely independent routine activity, defined as a modified Rankin Scale score of ≤1 at day 90 after stroke onset; symptomatic intracranial hemorrhage (ICH) occurring within 36 hours after stroke onset; and any ICH. We enrolled 127 patients (27 in the CO group and 100 in the non-CO group) with a median baseline NIHSS score of 13 (range, 4-30). The CO group had a higher baseline NIHSS score (median, 18 vs 12; P=.005). After multivariate adjustment, the CO group was inversely associated with early improvement (odds ratio [OR]=0.26; 95% confidence interval [CI]=0.09-0.72) and independence at day 90 (OR=0.23; 95% CI=0.05-0.73) and positively associated with any ICH (OR=3.11; 95% CI=1.23-8.48). Our findings indicate that CO identified by US in the emergency clinical setting is an independent predictor of unfavorable outcome and ICH following IV alteplase therapy.

Intravenous desmoteplase in patients with acute ischaemic stroke selected by MRI perfusion-diffusion weighted imaging or perfusion CT (DIAS-2): a prospective, randomised, double-blind, placebo-controlled study.

BACKGROUND: Previous studies have suggested that desmoteplase, a novel plasminogen activator, has clinical benefit when given 3-9 h after the onset of the symptoms of stroke in patients with presumptive tissue at risk that is identified by magnetic resonance perfusion imaging (PI) and diffusion-weighted imaging (DWI). METHODS: In this randomised, placebo-controlled, double-blind, dose-ranging study, patients with acute ischaemic stroke and tissue at risk seen on either MRI or CT imaging were randomly assigned (1:1:1) to 90 microg/kg desmoteplase, 125 microg/kg desmoteplase, or placebo within 3-9 h after the onset of symptoms of stroke. The primary endpoint was clinical response rates at day 90, defined as a composite of improvement in National Institutes of Health stroke scale (NIHSS) score of 8 points or more or an NIHSS score of 1 point or less, a modified Rankin scale score of 0-2 points, and a Barthel index of 75-100. Secondary endpoints included change in lesion volume between baseline and day 30, rates of symptomatic intracranial haemorrhage, and mortality rates. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, NCT00111852. FINDINGS: Between June, 2005, and March, 2007, 193 patients were randomised, and 186 patients received treatment: 57 received 90 microg/kg desmoteplase; 66 received 125 microg/kg desmoteplase; and 63 received placebo. 158 patients completed the study. The median baseline NIHSS score was 9 (IQR 6-14) points, and 30% (53 of 179) of the patients had a visible occlusion of a vessel at presentation. The core lesion and the mismatch volumes were small (median volumes were 10.6 cm(3) and 52.5 cm(3), respectively). The clinical response rates at day 90 were 47% (27 of 57) for 90 microg/kg desmoteplase, 36% (24 of 66) for 125 microg/kg desmoteplase, and 46% (29 of 63) for placebo. The median changes in lesion volume were: 90 microg/kg desmoteplase 14.0% (0.5 cm(3)); 125 microg/kg desmoteplase 10.8% (0.3 cm(3)); placebo -10.0% (-0.9 cm(3)). The rates of symptomatic intracranial haemorrhage were 3.5% (2 of 57) for 90 microg/kg desmoteplase, 4.5% (3 of 66) for 125 microg/kg desmoteplase, and 0% for placebo. The overall mortality rate was 11% (5% [3 of 57] for 90 microg/kg desmoteplase; 21% [14 of 66] for 125 microg/kg desmoteplase; and 6% [4 of 63] for placebo). INTERPRETATION: The DIAS-2 study did not show a benefit of desmoteplase given 3-9 h after the onset of stroke. The high response rate in the placebo group could be explained by the mild strokes recorded (low baseline NIHSS scores, small core lesions, and small mismatch volumes that were associated with no vessel occlusions), which possibly reduced the potential to detect any effect of desmoteplase. FUNDING: PAION Deutschland GmbH; Forest Laboratories.

Recanalization and reperfusion therapies for acute ischemic stroke.

Arterial recanalization and subsequent reperfusion have extensively demonstrated the ability to restore the brain function when performed shortly after acute ischemic stroke. Experimental and human studies have consistently demonstrated that early tissue reperfusion may limit ischemic tissue enlargement, leading to a reduced infarct size and favorable clinical outcome. However, arterial recanalization does not necessarily lead to brain tissue reperfusion. Lack of reperfusion after early recanalization may be caused by multiple downstream embolization, blockage of microcirculation due to non-reflow phenomenon or rapid recruitment of ischemic tissue before recanalization resulting in non-nutritional reperfusion. In some cases, sudden tissue reperfusion may be deleterious, leading to brain blood barrier disruption and hemorrhagic transformation or massive brain edema due to the so-called 'reperfusion injury'. In spite of this, recanalization represents the powerful predictor of stroke outcome and it is being increasingly used as a surrogate efficacy measurement in thrombolytic and other revascularization trials in acute stroke. Several emerging strategies have the potential to extend cerebral reperfusion therapy to larger numbers of patients, including patients presenting beyond the current 3-hour time window. Moreover, novel reperfusion approaches may improve the efficacy and safety of thrombolysis in a larger number of stroke patients. This review highlights recent advances in reperfusion treatments for acute ischemic stroke.

Rosiglitazone ameliorates tissue plasminogen activator-induced brain hemorrhage after stroke.

OBJECTIVE: Delayed thrombolytic therapy with recombinant tissue plasminogen activator (tPA) may exacerbate blood-brain barrier (BBB) breakdown after ischemic stroke and lead to catastrophic hemorrhagic transformation (HT). Rosiglitazone(RSG), a widely used antidiabetic drug that activates peroxisome proliferator-activated receptor-γ (PPAR-γ), has been shown to protect against cerebral ischemia through promoting poststroke microglial polarization toward the beneficial anti-inflammatory phenotype. However, whether RSG can alleviate HT after delayed tPA treatment remains unknown. In this study, we sort to examine the role of RSG on tPA-induced HT after stroke. METHODS AND RESULTS: We used the murine suture middle cerebral artery occlusion (MCAO) models of stroke followed by delayed administration of tPA (10 mg/kg, 2 hours after suture occlusion) to investigate the therapeutic potential of RSG against tPA-induced HT. When RSG(6 mg/kg) was intraperitoneally administered 1 hour before MCAO in tPA-treated MCAO mice, HT in the ischemic territory was significantly attenuated 1 day after stroke. In the tPA-treated MCAO mice, we found RSG significantly mitigated BBB disruption and hemorrhage development compared to tPA-alone-treated stroke mice. Using flow cytometry and immunostaining, we confirmed that the expression of CD206 was significantly upregulated while the expression of iNOS was down-regulated in microglia of the RSG-treated mice. We further found that the expression of Arg-1 was also upregulated in those tPA and RSG-treated stroke mice and the protection against tPA-induced HT and BBB disruption in these mice were abolished in the presence of PPAR-γ antagonist GW9662 (4 mg/kg, 1 hour before dMCAO through intraperitoneal injection). CONCLUSIONS: RSG treatment protects against BBB damage and ameliorates HT in delayed tPA-treated stroke mice by activating PPAR-γ and favoring microglial polarization toward anti-inflammatory phenotype.

Induction of matrix metalloproteinase, cytokines and chemokines in rat cortical astrocytes exposed to plasminogen activators.

Plasminogen activators are used in thrombolytic stroke therapy. However, it is increasingly recognized that they have other actions besides fibrinolysis. In this study, we assess potential pro-inflammatory effects of tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA) in rat cortical astrocytes. Both uPA and tPA induced rapid dose-dependent upregulation in MMP-2 and MMP-9, as demonstrated by zymography of conditioned media. In addition, a multiplex ELISA array demonstrated that patterned responses in chemokines and cytokines were also evoked. Exposure to tPA induced elevations in secreted MIP-2, MCP-1 and GRO/KC. Exposure to uPA induced elevations in secreted IFN-gamma, TNF-alpha, GMCSF, MIP-1alpha, MIP-2, MIP-3alpha, MCP-1, RANTES and fractalkine. These data suggest that plasminogen activators may trigger selected pro-inflammatory responses at the neurovascular interface. Whether these effects influence thrombolytic stroke therapy warrants further investigation.

Efficacy and safety of desmoteplase in acute ischemic stroke patients: A systematic review and meta-analysis.

BACKGROUND: Pending results from double-blind, multicenter, parallel-group, randomized trials, the benefit and safety of the novel plasminogen activator, desmoteplase remain undetermined. The aim of this meta-analysis was to help evaluate desmoteplase's efficacy and safety. METHODS: A thorough search was performed of the Cochrane Library, PubMed, and Embase from the inception of electronic data to March 2017, and double-blind, multicenter, parallel-group, randomized trials were chosen. We conducted a meta-analysis of studies investigating intravenous desmoteplase treatment of acute ischemic stroke patients 3 to 9 hours after symptom onset. Asymptomatic intracerebral hemorrhage, good clinical outcome at 90 days, and reperfusion 4 to 8 hours posttreatment were variables assessing efficacy; symptomatic intracerebral hemorrhage and death rates were measures of safety. RESULTS: Six trials involving 1071 patients thrombolyzed >3 hours postonset were included (600 received intravenous desmoteplase, 471 placebo). Desmoteplase was associated with increased reperfusion (odds ratio [OR] 1.57; 95% confidence interval [CI], 1.10-2.24; P = .01 vs control) and showed a tendency to increase asymptomatic intracerebral hemorrhage (OR 1.25; 95% CI, 0.97-1.62; P = .09 vs control), whereas there was no increase in symptomatic intracerebral hemorrhage and death rate with desmoteplase. However, there was no difference in the clinical response at 90 days (OR 1.14; 95% CI, 0.88-1.49; P = .31 vs control). Subgroup analysis showed that desmoteplase 90 µg/kg (OR 1.53; 95% CI, 1.07-2.21; P = .02 vs control) and 125 µg/kg (OR 4.07; 95% CI, 1.16-14.24; P = .03 vs control) were associated with an increase in reperfusion. Also, we found desmoteplase 90 µg/kg showed a tendency to increase asymptomatic intracerebral hemorrhage (OR 1.25; 95% CI, 0.95-1.63; P = .11 vs control). CONCLUSION: Intravenous desmoteplase is associated with a favorable reperfusion efficacy and acceptable safety in ischemic stroke treatment >3 hours after symptom onset. Well-designed randomized controlled trials with larger patient cohorts and a moderate dose of drugs are needed to further evaluate the true efficacy of desmoteplase in stroke patients. TRIAL REGISTRATION: URL: http://www.crd.york.ac.uk/PROSPERO; PROSPERO registration number: CRD42016037667).

Desmoteplase for Acute Ischemic Stroke: A Systematic Review and Metaanalysis of Randomized Controlled Trials.

INTRODUCTION: There is an unmet need to develop better treatments for acute ischemic stroke (AIS). Desmoteplase is a vampire bat saliva-derived analogue of human tissue plasminogen activator. It has higher fibrin selectivity and a longer half-life, compared to alteplase. We performed this metaanalysis to investigate the safety and efficacy of desmoteplase in AIS. METHOD: A computer literature search (PubMed, EMBASE, CENTRAL, Scopus, Web of science, and clinicaltrials.gov) was carried out. Data were extracted from eligible records and analyzed using RevMan software (version 5.3 for windows). Safety and efficacy endpoints were pooled as odds ratios (ORs) for the two groups. RESULT: Five randomized trials (n=821 patients) were pooled in the final analysis. The overall effect size favored desmoteplase over placebo in terms of reperfusion 4 to 24 hours posttreatment (OR 1.49, 95% CI [1.02, 2.19]). However, the pooled effect size did not favor either of the two groups in terms of good clinical outcome at 90 days (OR 1.16, 95% CI [0.86, 1.55]). Neither of the primary safety outcomes differed significantly between the two groups (symptomatic intracranial hemorrhage: OR 1.29, 95% CI [0.53, 3.16] and mortality within 90 days: OR 1.20, 95% CI [0.73, 1.97]). CONCLUSION: Current evidence suggests a favorable reperfusion effect for desmoteplase within 3 to 9 hours after AIS. Further large randomized trials, using a moderate dose between 90 µg/kg and 125 µg/kg, are required to translate this successful reperfusion into better clinical and quality of life outcomes for AIS patients.

Dose Escalation of Desmoteplase for Acute Ischemic Stroke (DEDAS): evidence of safety and efficacy 3 to 9 hours after stroke onset.

BACKGROUND AND PURPOSE: Desmoteplase is a novel plasminogen activator with favorable features in vitro compared with available agents. This study evaluated safety and efficacy of intravenous (IV) desmoteplase in patients with perfusion/diffusion mismatch on MRI 3 to 9 hours after onset of acute ischemic stroke. METHODS: DEDAS was a placebo-controlled, double-blind, randomized, dose-escalation study investigating doses of 90 microg/kg and 125 microg/kg desmoteplase. Eligibility criteria included baseline National Institute of Health Stroke Scale (NIHSS) scores of 4 to 20 and MRI evidence of perfusion/diffusion mismatch. The safety end point was the rate of symptomatic intracranial hemorrhage. Primary efficacy co-end points were MRI reperfusion 4 to 8 hours after treatment and good clinical outcome at 90 days. The primary analyses were intent-to-treat. Before unblinding, a target population, excluding patients violating specific MRI criteria, was defined. RESULTS: Thirty-seven patients were randomized and received treatment (intent-to-treat; placebo: n=8; 90 microg/kg: n=14; 125 microg/kg: n=15). No symptomatic intracranial hemorrhage occurred. Reperfusion was achieved in 37.5% (95% CI [8.5; 75.5]) of placebo patients, 18.2% (2.3; 51.8) of patients treated with 90 microg/kg desmoteplase, and 53.3% (26.6; 78.7) of patients treated with 125 microg/kg desmoteplase. Good clinical outcome at 90 days occurred in 25.0% (3.2; 65.1) treated with placebo, 28.6% (8.4; 58.1) treated with 90 microg/kg desmoteplase and 60.0% (32.3; 83.7) treated with 125 microg/kg desmoteplase. In the target population (n=25), the difference compared with placebo increased and was statistically significant for good clinical outcome with 125 microg/kg desmoteplase (P=0.022). CONCLUSIONS: Treatment with IV desmoteplase 3 to 9 hours after ischemic stroke onset appears safe. At a dose of 125 microg/kg desmoteplase appeared to improve clinical outcome, especially in patients fulfilling all MRI criteria. The results of DEDAS generally support the results of its predecessor study, Desmoteplase in Acute Ischemic Stroke (DIAS).

Comparative safety and efficacy of urokinase and recombinant tissue plasminogen activator for peripheral arterial occlusion: a meta-analysis.

STUDY OBJECTIVE: To evaluate differences in the efficacy and safety of recombinant tissue plasminogen activator (rt-PA) and urokinase in the treatment of peripheral arterial occlusion. DESIGN: Systematic review and meta-analysis of prospective comparative trials. DATA SOURCE: PubMed/MEDLINE database from 1966-October 2004. MEASUREMENTS AND MAIN RESULTS: The literature was systematically searched to identify prospective comparative trials of urokinase and rt-PA for the treatment of peripheral arterial occlusion. The primary outcome measure was successful complete lysis of the occlusion. Other outcome measures were hemorrhage (major, minor, or combined), intracranial hemorrhage, limb loss, and mortality. Six trials were identified, five of which were randomized. On meta-analysis, the rate of clot lysis was higher with rt-PA than with urokinase (odds ratio [OR] 1.54, 95% confidence interval [CI] 1.12-2.10, p=0.007). However, urokinase was associated with lower rates of minor (OR 0.52, 95% CI 0.28-0.97, p=0.04) and total (OR 0.51, 95% CI 0.29-0.91, p=0.02) bleeding. Rates of major hemorrhage, intracranial hemorrhage, limb loss, and mortality were similar between agents. CONCLUSION: Urokinase was less effective than rt-PA in successfully lysing acute peripheral arterial occlusion, but it was associated with lower rates of total and minor bleeding. Overall, rt-PA was a reasonable substitute for urokinase, now that urokinase has been removed from the market in the United States. However, judicious monitoring for minor bleeding is necessary.

Randomized adjuvant chemotherapy trial in high-risk, lymph node-negative breast cancer patients identified by urokinase-type plasminogen activator and plasminogen activator inhibitor type 1.

BACKGROUND: Most patients with lymph node-negative breast cancer are cured by locoregional treatment; however, about 30% relapse. Because traditional histomorphologic and clinical factors fail to identify the high-risk patients who may benefit from adjuvant chemotherapy, other prognostic factors are needed. In a unicenter study, we have found that levels of urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor type 1 (PAI-1) in the primary tumor are predictive of disease recurrence. Thus, we designed the Chemo N(0) prospective randomized multicenter therapy trial to investigate further whether uPA and PAI-1 are such prognostic factors and whether high-risk patients identified by these factors benefit from adjuvant chemotherapy. After 4.5 years, we present results of the first interim analysis. METHODS: We studied 556 patients with lymph node-negative breast cancer. The median follow-up was 32 months. All patients with low tumor levels of uPA (< or = 3 ng/mg of protein) and of PAI-1 (< or = 14 ng/mg of protein) were observed. Patients with high tumor levels of uPA (> 3 ng/mg of protein) and/or of PAI-1 (> 14 ng/mg of protein) were randomly assigned to combination chemotherapy or subjected to observation only. All statistical tests were two-sided. RESULTS: A total of 241 patients had low levels of uPA and PAI-1, and 315 had elevated levels of uPA and/or PAI-1. The estimated 3-year recurrence rate for patients with low tumor levels of uPA and PAI-1 (low-risk group) was 6.7% (95% confidence interval [CI] = 2.5% to 10.8%). This rate for patients with high tumor levels of uPA and/or PAI-1 (high-risk group) was 14.7% (95% CI = 8.5% to 20.9%) (P = 0.006). First interim analysis suggests that high-risk patients in the chemotherapy group benefit, with a 43.8% lower estimated probability of disease recurrence at 3 years than high-risk patients in the observation group (intention-to-treat analysis: relative risk = 0.56; 95% CI = 0.25 to 1.28), but further follow-up is needed for confirmation. CONCLUSIONS: Using uPA and PAI-1, we have been able to classify about half of the patients with lymph node-negative breast cancer as low risk, for whom adjuvant chemotherapy may be avoided, and half as high risk, who appear to benefit from adjuvant chemotherapy.